1. Technical Field
The present disclosure relates to systems and methods for investigating dissolution of pharmaceutical solids.
2. Background Art
Dissolution of a drug from the solid state in a solid oral dosage form is a key step in the absorption and eventual therapeutic effect of a drug. Once a potential drug has been identified, a proper solid form (e.g., polymorph, salt form) must be chosen. In choosing a proper solid form, certain behavioral properties must be taken into consideration such as, for example, dissolution rates, equilibrium solubility, physical and chemical stability. Dissolution rates depend on the hydrodynamics of the fluid adjacent to the solid state drug. Hydrodynamics of most standard dissolution test methods are not fully understood.
Lack of hydrodynamic data makes studying the hydrodynamic impact on any interesting phenomena that could arise (e.g., salt form changes, polymorph changes) challenging in predicting bioavailability in humans. For example, using current systems/methods, when unexpected change in dissolution rates during standard testing occurs, typically an analyst cannot easily observe physical changes in real time associated with changes in dissolution. Also, current dissolution testing systems/methods require large amounts of test sample. This creates a serious burden on a typical research analyst or research group since they may receive only a few milligrams of a new compound designated to undergo several tests.
There are many dissolution methods currently used for characterizing pharmaceutical solids. Standard USP (United States Pharmacopoeia) methods include USP Type I, II and IV. The USP Type I method is commonly known as the basket method, in which the tablet is placed in a basket that is rotated in a fixed volume bath of dissolution medium. USP Type II method is commonly known as the paddle method in which the solid is placed at the bottom of the dissolution bath while a paddle agitator aids in dissolution. USP Type IV method is a flow-through device in which the solution flows through a cell in which the solid is suspended. These standard methods, however, fail to appreciate or consider the exact hydrodynamics since the fluid flow characteristics are complicated and time dependent.
Currently, other non-USP methods include Wood's die apparatus, and various flow-through devices found in pharmaceutical literature. The Wood's die apparatus is a rotating device in which the solid test sample is compressed such that the surface area of the solid remains constant. The device is placed in a dissolution bath and allowed to rotate. The hydrodynamics of this system have been thoroughly described by Levich. (See, e.g., V. Levich. Physicochemical Hydrodynamics, Prentice-Hall, Englewood Cliffs, 1962.) In 1975 Nelson and Shah described a flow cell in which a pharmaceutical sample was compressed and fluid was allowed to flow over the top of the compressed pharmaceutical. (See, e.g., A. C. Shah and K. G. Nelson, Evaluation of a convective diffusion drug dissolution rate model, Journal of Pharmaceutical Sciences 64: 1518-20 (1975)). The hydrodynamics of this system have been described along with similar flow though devices by other authors including Sun and Missel. (See, e.g., W. Sun, C. K. Larive and M. Z. Southard, A mechanistic study of danazol dissolution in ionic surfactant solutions, Journal of Pharmaceutical Sciences 92: 424-435 (2003); and P. J. Missel, L. E. Stevens and J. W. Mauger. Reexamination of convective diffusion/drug dissolution in a laminar flow channel: Accurate prediction of dissolution rate. Pharmaceutical Research 21: 2300-2306 (2004)). In each of the aforementioned descriptions, whether the hydrodynamics are fully understood or not, none describes a system capable of visualizing the pharmaceutical solid during dissolution.
Visualization is a critical aspect to gaining a thorough understanding of the dissolution process, particularly if the solid undergoes some kind of transition such as, for example, polymorph change, amorphous to crystalline transition, or a salt form conversion. One flow cell apparatus/method described by Van Der Weerd, does allow for visualization of the tablet during dissolution by FTIR imaging. (See, J. van der Weerd, K. L. A. Chan and S. G. Kazarian, An innovative design of compaction cell for in situ FTIR imaging of tablet dissolution, Vibrational Spectroscopy 35: 9-13 (2004); J. van der Weerd and S. G. Kazarian, Combined approach of FTIR imaging and conventional dissolution tests applied to drug release, Journal of Controlled Release 98: 295-305 (2004); and J. Van Der Weerd and S. G. Kazarian, Release of poorly soluble drugs from HPMC tablets studied by FTIR imaging and flow-through dissolution tests, Journal of Pharmaceutical Sciences 94: 2096-2109 (2005)). While visualization is possible using the aforementioned systems/methods, the disclosed systems/techniques fail to appreciate or consider complete characterization of the hydrodynamics of the system. Similarly, various techniques have been described for a flow-through dissolution apparatus that inadequately address hydrodynamics. (See, e.g., W. C. G. Butler and S. R. Bateman, A flow-through dissolution method for a two component drug formulation where the actives have markedly differing solubility properties, International Journal of Pharmaceutics 173: 211-219 (1998); L. Peltonen, P. Liljeroth, T. Heikkila, K. Kontturi and J. Hirvonen, Dissolution testing of acetylsalicylic acid by a channel flow method-correlation to USP basket and intrinsic dissolution methods, European Journal of Pharmaceutical Sciences 19: 395-401 (2003); E. D. Carlson, M. Petro and S. H. Nguyen, Methods and systems for dissolution testing, and use in drug candidate evaluation, U.S. Pat. Appl. Publ., (USA). Us, 2004, pp. 37; G. J. Havrilla, T. C. Miller, B. P. Warner, C. L. Lewis, C. A. Mahanand, and C. A. Wells, Flow method and apparatus for screening chemicals using micro x-ray fluorescence, U.S. Pat. Appl. Publ., (USA) Us, 2004, pp. 9; and L. Peltonen, P. Liljeroth, T. Heikkila, K. Kontturi and J. Hirvonen, A novel channel flow method in determination of solubility properties and dissolution profiles of theophylline tablets, Journal of Drug Delivery Science and Technology 14: 389-394 (2004).)
Salt selection is an important component of the drug development process. Effective salt selection can lead to a significant increase in solubility over free base/free acid form, which may result in superior bioavailability. The solubility advantage and expected increase in bioavailability are often lost upon the conversion of the salt form to a less soluble form, including the sparingly soluble free acid/base form. When choosing a salt form, aqueous solubility alone is not enough information to understand the full solubility advantage of a salt form due to the propensity to convert to a lower solubility form during solubility studies. To fully understand the potential in vivo performance of a selected sample, the salt solubility, dissolution rate, conversion rate and precipitation at multiple pH values of a given sample should be explored. By studying the combination of solubility, dissolution, conversion and precipitation effects, bioavailability of salt forms can be better predicted.
It is commonly known that highly soluble salts of basic drugs are prone to conversion to the HCl salt in the stomach which has a lower solubility due to common ion effect. In the intestines, due to the increased pH, salts of basic drugs can undergo a conversion to the sparingly soluble free base form. It is of general interest to determine how and when these conversions occur and if they occur on a time scale relative to absorption. Currently, the conditions under which these phenomena should be optimally studied are not fully understood. Knowledge of hydrodynamic conditions during dissolution is paramount to studying these effects due to the combination of mass and momentum transport coupled with reactive dissolution that occurs.
The hydrodynamics of most standard pharmaceutical dissolution test methods are not fully understood, which makes studying the hydrodynamic impact on any interesting phenomena that could arise (e.g., salt form changes, polymorph changes) nearly impossible. When there is an unexpected change in dissolution rates during standard testing, the scientist cannot easily observe any visual changes that accompany such a change. More importantly, currently available standard methods require a large amount of material. With the advancements made in high throughput screening, dissolution testing should ideally be studied early in the development process using very little solid.
These and other disadvantages and/or limitations are addressed and/or overcome by the systems and methods of the present disclosure.